Unilateral Leptospiral Pneumonia and Cold Agglutinin Disease

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peritoneum as an early complication after adenotonsillectomy. J Laryngol Otol 1995; 109:440 – 441 Uva J. Spontaneous pneumothoraces, pneumomediastinum, and pneumoperitoneum: consequences of smoking crack cocaine. Pediatr Emerg Care 1997; 13:24 –26 Williams NMA, Watkin DFL. Spontaneous pneumoperitoneum and other causes of intraperitoneal free gas. Postgrad Med J 1997; 73:531–537 Lopez-Viego MA, Cornell JM. Pneumoperitoneum and signs of peritonitis from a pleuroperitoneal shunt. Surg 1992; 111:228 –229 Egan M, Boutros A. Pneumoperitoneum following tension pneumothorax: report of two cases. Crit Care Med 1975; 3:170 –172 Makinen MT, Yli-Hankala A. The effect of laparoscopic cholecystectomy on respiratory compliance as determined by continuous spirometry. J Clin Anesth 1996; 8:119 –122

Unilateral Leptospiral Pneumonia and Cold Agglutinin Disease* Barbara Bowsher, MD, CPT, MC, USAR; Charles W. Callahan, DO, LTC, MC, USA, FCCP; Donald A. Person, MD, COL, MC, USA; and Lynne Ruess, MD

Pneumonia that is unresponsive to appropriate antibiotic therapy suggests an infection due to more unusual or resistant organisms. In this report, a child with unilateral pneumonia, pleural effusion, and anti-I cold hemagglutinin antibodies is presented. The usual causes of this clinical picture were suspected and treated, but the child did not improve. Features of her history suggested a more unusual etiology, and a diagnosis of leptospirosis was made. A brief discussion of leptospiral disease in children is provided. (CHEST 1999; 116:830 – 832) Key words: anti-I cold hemagglutinin; leptospirosis; pneumonia Abbreviations: hpf 5 high power field; TAMC 5 Tripler Army Medical Center

that is unresponsive to appropriate antibiotic P neumonia therapy suggests an infection due to more unusual or resistant organisms. Bacterial, viral, mycobacterial, and fungal lung infections should be considered as possible etiologies in this clinical setting. Here, a case of a child with unilateral

*From the Departments of Pediatrics (Drs. Bowsher and Callahan), Clinical Investigation (Dr. Person), and Radiology (Dr. Reuss), Tripler Army Medical Center, Honolulu, HI. The opinions expressed are those of the authors and do not necessarily reflect the position or policy of the Department of Defense, the Department of the Army, or the Army Medical Department. Manuscript received September 29, 1998; revision accepted April 7, 1999. Correspondence to: Charles W. Callahan, DO, LTC, MC, USA, FCCP, Tripler Army Medical Center (MCHK-PE), 1 Jarrett White Rd, Honolulu, HI 96859-5000 830

pneumonia, pleural effusion, and anti-I cold hemagglutinin antibodies is presented. The child was suspected of having Mycoplasma pneumonia, but was found to have leptospirosis with an unusual pulmonary presentation.

Case Report A previously healthy 5-year-old Chamorro girl presented initially to an emergency department in Guam with fever to 40°C and symptoms of an upper respiratory infection. She was seen by a pediatrician the following day, with fever, vomiting, cough, and pleuritic chest pain that was attributed to a viral syndrome. Two days later, she returned with persistent fever, progressive cough, decreased oral intake, and the onset of back and shoulder pain. A chest radiograph revealed right upper and middle lobe pneumonia with pleural effusion. Her WBC count was 7.9 3 103/mL, including 7% segmented neutrophils, 76% band forms, 4% monocytes, 5% metamyelocytes, and 2% myelocytes. Her hemoglobin was 11.2 g/dL, and platelets were 229 3 103/mL. She was treated with IV oxacillin and ceftriaxone. She improved slightly, but on her third hospital day she developed increased fever, tachypnea, and decreased urine output. A repeat chest radiograph was unchanged, but CT of the chest revealed a large right sided pleural effusion with a mild left mediastinal shift. A chest tube was inserted, draining 400 mL of hazy, yellow exudative fluid that clotted (total protein, 3.8 g/dL; lactic dehydrogenase, 2,525 U/L; and specific gravity, 1.020). At this point, her antibiotic therapy was changed to oxacillin and gentamicin, and she was emergency evacuated to Tripler Army Medical Center (TAMC). Upon arrival at TAMC, her heart rate was 144 beats/min; respiratory rate, 50 breaths/min; BP, 111/40 mm Hg; and temperature, 37.2°C. She was alert and oriented. Her sclerae were icteric, and conjunctivae were injected. A right sided chest tube was in place, and auscultation revealed fine crackles on the right with clear breath sounds on the left. A cardiovascular examination was significant for tachycardia. An abdominal examination revealed hepatomegaly 2 cm below the right costal margin, without splenomegaly. Her skin was jaundiced. A laboratory evaluation revealed a WBC count of 15.6 3 103/ mL; hemoglobin, 8.4 g/dL; hematocrit, 24.5%; and platelets, 33 3 103/mL. On urinalysis, RBCs were 27/high power field (hpf). Her prothrombin time was 13.0 s (normal), and partial thromboplastin time was 27 s (normal). Her aspartate aminotransferase level was elevated at 185 U/L. Her amylase was 165 U/L (normal), and lipase was elevated at 1,183 U/L. Serum albumin was 2.1 g/dL, and total bilirubin was 5.1 mg/dL. Creatinine was 0.9 mg/dL, and her BUN was 21 mg/dL. The pleural fluid analysis was repeated, revealing a pH of 7.5; glucose, 21 mg/dL; total protein, 4.5 g/dL; lactic dehydrogenase, 17,310 U/L; WBC, 800/hpf; and RBC, 1,790/hpf. The result of a qualitative test for cold agglutinins performed at bedside was positive. (Two milliliters of whole blood were placed into a blue-top sodium citrate tube and mixed. The side of the tube was noted to have a uniform coat of blood against a white background. The tube was then placed on ice for 3 to 5 min, and removed. When held against a white background again, the granular appearance of cold agglutinated blood was noted. The agglutination resolved when the tube was rewarmed.) Her chest radiograph revealed right upper and middle lobe airspace disease with pleural effusion (Fig 1). Repeat CT of the chest revealed dense consolidation of most of the right lung with air bronchograms and pleural effusion (Fig 2, top and bottom). Treatment with nafcillin, cefotaxime, and erythromycin was begun. Over the next 36 h, her peripheral smear showed signs of hemolysis. Her hemoglobin dropped to 6 g/dL; hematocrit, 15.8%; red (blood cell) distribution width, 15.4% (high); and total bilirubin rose to 23.3 mg/dL (unconjugated, 1.6 mg/dL; conjuSelected Reports

Figure 1. Portable chest radiograph (anterior/posterior) on admission to our institution. A right apical chest tube is in place. There is consolidation of the right upper and middle lobes with air bronchograms. There is a moderate right pleural effusion seen laterally. The left lung is clear. gated, 15.8 mg/dL; and D bilirubin, 5.8 mg/dL). Her BUN and creatinine peaked at 37 mg/dL and 0.9 mg/dL, respectively. Her prothrombin time climbed to 15.9 s. Her aspartate aminotransferase was elevated at 200 U/L, and g-glutamyl transpeptidase rose to 152 U/L. The hemolysis was found to be due to an anti-I antibody (not quantified). Her bone marrow aspirate and biopsy specimen were interpreted as hyperplastic. Because her clinical picture was evolving to be more consistent with leptospirosis, penicillin was added to the antibiotic regimen. Her autoimmune hemolysis was treated with IV “pulse” doses of high-dose methylprednisolone, 30 mg/kg every 8 hours, resulting in a dramatic increase in platelet count, a resolution of hemolysis, and clearance of the pneumonic process. Further history obtained during her hospitalization reinforced the suspicion of leptospirosis. Her family lived at the bottom of a hill below a pig farm in Guam, with a stream running near their house. The child denied playing in the stream, although her mother said that with heavy rains the stream flooded and ran through their home. The family also recalled the presence of a dead rat in the front yard within the previous month. The results of serial mycoplasma antibodies were negative. The results of all blood cultures and cultures of the pleural effusion were negative. The result of a urine culture for Leptospira was negative. She completed 1 week of treatment with nafcillin and cefotaxime, and 10 days of treatment with penicillin and erythromycin. Her radiographic findings improved, and by 2 weeks she had completely recovered. Serum samples obtained at 1 and 2 weeks after the onset of her illness were negative for leptospiral antibodies, both by direct hemagglutination (State of Hawaii Department of Health, Honolulu, HI) and microscopic agglutination (Centers for Disease Control and Prevention, Atlanta, GA.) A third serum sample (obtained 23 days after the onset of symptoms) tested positive by mircoscopic agglutination (Centers for Disease Control and Prevention) at a titer of 1:100 for Leptospira interogans serovar Bratislava, strain Jez-bratislava, a positive seroconversion. There were . 20 serovar/strain assays performed on each of the three sera, and all were negative except the above, which is diagnostic for leptospirosis.

Discussion Leptospirosis has a wide distribution and is the most common zoonosis in the world. It is of high endemnicity in

Figure 2. Axial CT image immediately inferior to the carina in both lung (top) and soft tissue (bottom) windows. There is consolidation of the right upper lobe with air bronchograms. A dependent pleural effusion and chest tube are seen. There are no abnormalities on the left.

the Pacific Islands. Human infection occurs after exposure to water contaminated by the urine of infected animals (usually rats, pigs, and dogs). The onset of leptospirosis is sudden, with influenza-like and GI symptoms. Weil’s disease is the more severe, icteric form of leptospirosis, and it does not occur in . 10% of patients with this infection. It is usually characterized by hepatitis, nephritis, and thrombocytopenia.1–3 The organism is usually sensitive to penicillin, although erythromycin is also considered effective. Thus, her clinical response may reflect a sufficient duration of effective therapy, rather than the relative efficacy of penicillin vs erythromycin.4 Pulmonary involvement is usually mild; in adults, it is characterized by mild hemoptysis or incidental radiographic findings.4 Our patient had epidemiologic evidence to suggest leptospirosis, the clinical picture of Weil’s disease, as well as positive leptospiral antibodies. She also had pancreatitis, a recognized complication of leptospirosis in children.1–3,5 Her serum leptospira titers were positive, and L interogans serovar Bratislava is a well-known cause of porcine-associated leptospirosis in the Pacific Basin. Her primary problem, however, was pulmonary disease (specifically, unilateral pneumonia with pleural effusion). CHEST / 116 / 3 / SEPTEMBER, 1999

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Unilateral pneumonia with effusion is common in pediatrics. There are a variety of bacterial etiologic agents that may lead to this clinical picture, including Streptococcus pneumoniae, Staphylococcus aureus, and invasive Haemophilus influenza.6 Disease from Mycoplasma pneumoniae may also produce unilateral pneumonia with pleural effusion.7 In addition, M pneumoniae may also cause hemolytic anemia related to cold agglutinins (anti-I antibody), thrombocytopenia, mild hepatitis, pancreatitis, and GI symptoms.7 Our patient’s initial course was typical for a complicated Mycoplasma infection, thus her early treatment included macrolide therapy. A lack of response to therapy, the severity of her associated symptoms, and the absence of measurable antibody titers to M pneumoniae on serial examinations suggested another etiology. Infection due to leptospirosis is thought to cause a systemic vasculitis, with damage to the capillary endothelium being the main site of the vascular damage. Focal hemorrhage of the tracheobronchial tree, parenchyma, diaphragm, and pleural surfaces have been reported with pleural effusions that are exudative and occasionally hemorrhagic. Radiographic abnormalities are most commonly noted in the first week of the disease in 6 to 10% of adults, and they are usually due to scattered alveolar hemorrhage in a “snowflake-like” or “mottling spot” pattern, most frequently in the lower lobes.8 In a series of 58 patients with leptospirosis and lung disease, radiographic abnormalities were noted in 37 patients (64%). All had bilateral disease, seven had pleural effusion (19%), and in six patients it was right sided.9 In a recent series of 43 children with leptospirosis, 3 patients developed hemorrhagic pulmonary disease, and it was the cause of the single death in the series.10 Pneumonitis with pleural effusions, albeit much less severe than that reported here, has been observed in three of nine children hospitalized with leptospirosis at TAMC in the past 3 years.1–3 The clinical presentation of this patient was also complicated by a hemolytic anemia. Anemia and thrombocytopenia are commonly reported with leptospirosis. Hemolysis is less common, and the mechanism is not well understood. This contributed to the confusion in the initial diagnosis for our patient. We also report what we believe to be the first association of leptospirosis with hemolysis due to anti-I hemagglutinin disease. Cold hemolysis is induced by IgM antibodies that bind to the RBC I/I antigen system.11 Although cold hemagglutinin disease may be associated with infections due to Epstein-Barr virus, cytomegalovirus, and mumps, anti-I hemagglutinin is most commonly associated with M pneumoniae.7 Pneumonia that is unilateral with pleural effusion and associated with cold hemagglutinin disease due to anti-I IgM would lead almost any clinician to think of Mycoplasma infection and treat accordingly. However, leptospirosis is an infection that causes generalized vasculitis with a wide array of clinical manifestations. It should be suspected, tested for, and treated in endemic areas when the history suggests the appropriate risk factors for zoonotic infection. 832

References 1 Person DA, Burnett MW. Leptospirosis: Tripler Army Medical Center. Medical Surveillance Monthly Report 1996; 2:7–10 2 Musgrave JE, Person DA. Acute renal failure in children due to leptospirosis. Pac Health Dialog 1996; 3:200 –201 3 Person DA. Leptospirosis in the Pacific: Tripler Army Medical Center. Medical Surveillance Monthly Report: 1998; 4:12–14 4 Feigin RD, Anderson DC. Leptospirosis. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases. Philadelphia, PA: WB Saunders, 1998; 1529 –1542 5 O’Brien MM, Vincent JM, Person DA, et al. Leptospirosis and pancreatitis: a report of ten cases. Pediatr Infect Dis J 1998; 17:436 – 438 6 Schidlow DV, Callahan CW. Pneumonia. Pediatr Rev 1996; 17:300 –309 7 Fernald GW. Infections of the respiratory tract due to Mycoplasma pneumoniae. In: Chernick V, Boat TF, Kendig EL, eds. Kendig’s disorders of the respiratory tract in children. Philadelphia, PA: WB Saunders, 1998; 526 –532 8 O’Neil KM, Rickman LS, Lazarus AA. Pulmonary manifestations of leptospirosis. Rev Infect Dis 1991; 13:705–709 9 Im J, Yeon KM, Han MC, et al. Leptospirosis of the lung: radiographic findings in 58 patients. Am J Radiol 1989; 152:955–959 10 Marotto PCF, Marotto MS, Santos DL, et al. Outcome of leptospirosis in children. Am J Trop Med Hyg 1997; 56:307– 310 11 Schrieber AD, Gill FM, Manno AD. Hemolytic anemia. In: Nathan DG, and Oski FA, eds. Hematology of infancy and childhood. Philadelphia, PA: WB Saunders, 1993; 495–510

Richter’s Transformation Presenting as an Obstructing Endobronchial Lesion* Deborah A. Milkowski, CPT, MC, USAF; Brian D. Worley, MAJ, MC, USA; and Michael J. Morris, LTC, MC, USA

A 60-year-old man with chronic lymphocytic leukemia presented to our institution with a recurring lingular pneumonia. On fiberoptic bronchoscopy, the patient was found to have an endobronchial mass obstructing the lingula and left upper lobe. Biopsy specimens of the mass demonstrated anaplastic large cell lymphoma consistent with Richter’s transformation. Only one case of endobronchial Richter’s transformation has been previously reported in the literature. This was described as peribronchial and endobronchial leukemic infiltrates within the bronchial mucosa. We report the first case of an obstructive endobronchial mass secondary to Richter’s transformation. The endobronchial mass was treated with a Nd-YAG laser to maintain airway patency while the patient underwent chemotherapy, resulting in complete resolution of the mass within the airway. (CHEST 1999; 116:832– 835) Selected Reports